The miR-98-3p/JAG1/Notch1 axis mediates the multigenerational inheritance of osteopenia caused by maternal dexamethasone exposure in female rat offspring

다국어 초록 (Multilingual Abstract)

As a synthetic glucocorticoid, dexamethasone is widely used to treat potential premature delivery and related diseases. Our previous studies have shown that prenatal dexamethasone exposure (PDE) can cause bone dysplasia and susceptibility to osteoporosis in female rat offspring. However, whether the effect of PDE on bone development can be extended to the third generation (F3 generation) and its multigenerational mechanism of inheritance have not been reported. In this study, we found that PDE delayed fetal bone development and reduced adult bone mass in female rat offspring of the F1 generation, and this effect of low bone mass caused by PDE even continued to the F2 and F3 generations. Furthermore, we found that PDE increases the expression of miR-98-3p but decreases JAG1/Notch1 signaling in the bone tissue of female fetal rats. Moreover, the expression changes of miR-98-3p/JAG1/Notch1 caused by PDE continued from the F1 to F3 adult offspring. Furthermore, the expression levels of miR-98-3p in oocytes of the F1 and F2 generations were increased. We also confirmed that dexamethasone upregulates the expression of miR-98-3p in vitro and shows targeted inhibition of JAG1/Notch1 signaling, leading to poor osteogenic differentiation of bone marrow mesenchymal stem cells. In conclusion, maternal dexamethasone exposure caused low bone mass in female rat offspring with a multigenerational inheritance effect, the mechanism of which is related to the inhibition of JAG1/Notch1 signaling caused by the continuous upregulation of miR-98-3p expression in bone tissues transmitted by F2 and F3 oocytes.

참고문헌 (Reference)

1 Gong, X., "miRNA320a-3p/RUNX2 signal programming mediates the transgenerational inheritance of inhibited ovarian estrogen synthesis in female offspring rats induced by prenatal dexamethasone exposure" 165 : 105435-, 2021

2 Li, L., "miR-148a/LDLR mediates hypercholesterolemia induced by prenatal dexamethasone exposure in male offspring rats" 395 : 114979-, 2020

3 Skinner, M. K., "What is an epigenetic transgenerational phenotype? F3 or F2" 25 : 2-6, 2008

4 Daxinger, L., "Understanding transgenerational epigenetic inheritance via the gametes in mammals" 13 : 153-162, 2012

5 Matthews, S. G., "Transgenerational inheritance of stress pathology" 233 : 95-101, 2012

6 Liberman, N., "Transgenerational epigenetic inheritance : from phenomena to molecular mechanisms" 59 : 189-206, 2019

7 Frantz, E. D., "Transgenerational endocrine pancreatic adaptation in mice from maternal protein restriction in utero" 132 : 110-116, 2011

8 Honjo, T., "The shortest path from the surface to the nucleus : RBP-J kappa/Su(H)transcription factor" 1 : 1-9, 1996

9 Chen, Y., "Sex difference in adrenal developmental toxicity induced by dexamethasone and its intrauterine programming mechanism" 174 : 105942-, 2021

10 Crowther, C. A., "Repeat doses of prenatal corticosteroids for women at risk of preterm birth for improving neonatal health outcomes" 7 : CD003935-, 2015

11 Mckinlay, C. J., "Repeat antenatal glucocorticoids for women at risk of preterm birth : a Cochrane Systematic Review" 206 : 187-194, 2012

12 Wagner, K. D., "RNA induction and inheritance of epigenetic cardiac hypertrophy in the mouse" 14 : 962-969, 2008

13 Kim, D. R., "Prenatal programming of mental illness : current understanding of relationship and mechanisms" 17 : 5-, 2015

14 Moisiadis, V. G., "Prenatal glucocorticoid exposure modifies endocrine function and behaviour for 3 generations following maternal and paternal transmission" 7 : 11814-, 2017

15 Sheen, J. M., "Prenatal dexamethasone-induced programmed hypertension and renal programming" 132 : 41-48, 2015

16 Chen, G., "Prenatal dexamethasone exposure-induced a gender-difference and sustainable multi-organ damage in offspring rats via serum metabolic profile analysis" 316 : 136-146, 2019

17 Lv, F., "Prenatal dexamethasone exposure induced ovarian developmental toxicity and transgenerational effect in rat offspring" 159 : 1401-1415, 2018

18 Fullston, T., "Paternal obesity initiates metabolic disturbances in two generations of mice with incomplete penetrance to the F2 generation and alters the transcriptional profile of testis and sperm microRNA content" 27 : 4226-4243, 2013

19 Zhu, F., "PKCdelta is required for Jagged-1induction of human mesenchymal stem cell osteogenic differentiation" 31 : 1181-1192, 2013

20 Schuiling, K. D., "Osteoporosis update" 56 : 615-627, 2011

21 Blair, H. C., "Osteoblast differentiation and bone matrix formation in vivo and in vitro" 23 : 268-280, 2017

22 Murphy, K. E., "Multiple courses of antenatal corticosteroids for preterm birth (MACS): a randomised controlled trial" 372 : 2143-2151, 2008

23 Yohn, N. L., "Multigenerational and transgenerational inheritance of drug exposure : The effects of alcohol, opiates, cocaine, marijuana, and nicotine" 118 : 21-33, 2015

24 Neves, F. M., "Morphometric evaluation of the fetal rat liver after maternal dexamethasone treatment: effect on the maturation of erythroid and megakaryocytic cells" 42 : 483-489, 2013

25 Qu, X., "MiR-199b-5p inhibits osteogenic differentiation in ligamentum flavum cells by targeting JAG1 and modulating the Notch signalling pathway" 21 : 1159-1170, 2017

26 Ge, Z. J., "Maternal diabetes mellitus and the origin of non-communicable diseases in offspring : the role of epigenetics" 90 : 139-, 2014

27 Shangguan, Y., "Low-activity programming of the PDGFRbeta/FAK pathway mediates H-type vessel dysplasia and high susceptibility to osteoporosis in female offspring rats after prenatal dexamethasone exposure" 185 : 114414-, 2021

28 Bellon, M., "JAG1 overexpression contributes to Notch1 signaling and the migration of HTLV-1-transformed ATL cells" 11 : 119-, 2018

29 Stenz, L., "Intergenerational transmission of DNA methylation signatures associated with early life stress" 19 : 665-675, 2018

30 Zhou, D. A., "Influence of glucocorticoids on the osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells" 15 : 239-, 2014

31 Xiao, H., "Increased H3K27ac level of ACE mediates the intergenerational effect of low peak bone mass induced by prenatal dexamethasone exposure in male offspring rats" 9 : 638-, 2018

32 Chang, K. P., "Incidence of hip and other osteoporotic fractures in elderly men and women : Dubbo Osteoporosis Epidemiology Study" 19 : 532-536, 2004

33 Bouxsein, M. L., "Guidelines for assessment of bone microstructure in rodents using micro-computed tomography" 25 : 1468-1486, 2010

34 Marciniak, B., "Glucocorticoids in pregnancy" 12 : 750-757, 2011

35 Moisiadis, V. G., "Glucocorticoids and fetal programming part 1 : Outcomes" 10 : 391-402, 2014

36 Beach, R. S., "Gestational zinc deprivation in mice:persistence of immunodeficiency for three generations" 218 : 469-471, 1982

37 Rigoutsos, I., "Gene-expression forum : Decoy for microRNAs" 465 : 1016-1017, 2010

38 Huntzinger, E., "Gene silencing by microRNAs : contributions of translational repression and mRNA decay" 12 : 99-110, 2011

39 Wolffe, A. P., "Epigenetics: regulation through repression" 286 : 481-486, 1999

40 Migicovsky, Z., "Epigenetic memory in mammals" 2 : 28-, 2011

41 Clarke, H. J., "Epigenetic inheritance through the female germ-line : The known, the unknown, and the possible" 43 : 106-116, 2015

42 Laires, P. A., "Epidemiology of hip fractures and its social and economic impact. update 2014" 40 : 223-230, 2015

43 Skinner, M. K., "Endocrine disruptors in 2015 : Epigenetic transgenerational inheritance" 12 : 68-70, 2016

44 Reagan-Shaw, S., "Dose translation from animal to human studies revisited" 22 : 659-661, 2008

45 Forhead, A. J., "Differential effects of maternal dexamethasone treatment on circulating thyroid hormone concentrations and tissue deiodinase activity in the pregnant ewe and fetus" 148 : 800-805, 2007

46 Liu, M., "Decreased H3K9ac level of StAR mediated testicular dysplasia induced by prenatal dexamethasone exposure in male offspring rats" 408 : 1-10, 2018

47 Nobta, M., "Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling" 280 : 15842-15848, 2005

48 Chen, Z., "Course-, dose-, and stage-dependent toxic effects of prenatal dexamethasone exposure on long bone development in fetal mice" 351 : 12-20, 2018

49 Stagi, S., "Bone metabolism in children and adolescents : main characteristics of the determinants of peak bone mass" 10 : 172-179, 2013

50 Sliwa, E., "Bone development of suckling piglets after prenatal, neonatal or perinatal treatment with dexamethasone" 94 : 293-306, 2010

51 Bloom, S. L., "Antenatal dexamethasone and decreased birth weight" 97 : 485-490, 2001

52 Haram, K., "Antenatal corticosteroid treatment : factors other than lung maturation" 30 : 1437-1441, 2017

53 Mitchell, E., "Alagille Syndrome" 22 : 625-641, 2018

54 Sun, K., "Adult-specific functions of animal microRNAs" 14 : 535-548, 2013

55 Kamalakar, A., "A non-canonical JAGGED1 signal to JAK2 mediates osteoblast commitment in cranial neural crest cells" 54 : 130-138, 2019